The overarching goal of the project is to develop a population risk-stratification tool that will allow efficacious and cost-effective lung cancer screening. Lung cancer represents an ideal malignancy for screening because of its prevalence, identifiable risk groups (current/former smokers) and ability to surgically cure the disease if diagnosed early. However, there are no robust screening techniques with options such as CT scans fraught with cost and harm from large numbers of false positives. One attractive approach is to exploit field carcinogenesis, the concept that the same genetic/environmental milieu that results in a lesion in one area of the lung will impact upon the entire aerodigestive mucosa. The buccal (cheek) mucosa is a molecular mirror of lung carcinogenesis, although current techniques are inadequate to translate this phenomenon into a minimally intrusive screening test. Our preliminary data show that the alteration of nanoscale architecture in buccal cells is exquisitely sensitive to field carcinogenesis and, hence, may serve as a robust biomarker for lung cancer. These nanoarchitectural changes can be detected in a practical and highly accurate fashion via a novel biophotonics technology, partial wave spectroscopic (PWS) microscopy. In this study, we will refine PWS technology, develop a prediction rule based on the PWS-detectable nanoscale alterations that is optimized for early stage, curable lung cancer. We will validate our preliminary data that there is no confounding with regards to demographics, risk factors (e.g. smoking intensity) and non-lung primary cancers. Finally, we will prospectively validate buccal PWS in a case control and a cohort studies. This project will provide the requisite data for future definitive large scale multicenter validation trials that could unequivocally prove the efficacy of buccal PWS analysis as the first line of screening for lung cancer allowing rational use of more expensive or intrusive tools such as CT scans or bronchoscopy. This novel paradigm could transform the clinical practice of lung cancer screening and thereby mitigate the large toll of this malignancy in Americans.